Project Summary. Anxiety disorders affect more than 40 million Americans and represent a major public health burden. The predictability of threat plays a significant role in theoretical models of anxiety disorders and is an important distinguishing factor between the emotional states of fear and anxiety. Fear is associated with imminent, present threat whereas anxiety is associated with unpredictable, future threat. This distinction is reflected in the NIMH Research Domain Criteria (RDoC) initiative as ?acute? and ?potential? threat, respectively. The extant literature has implicated intolerance of uncertainty (IU), or fear of the unknown, as an important individual difference variable associated with increased response to unpredictable threat. Further, IU is considered a transdiagnostic risk factor for the development and maintenance of anxiety disorders, with recent work suggesting that IU may be one of the fundamental fears underlying anxiety and neuroticism. A key focus of the NIMH RDoC initiative is to identify and integrate risk factors for mental disorders with neural and/or psychophysiological indictors or biomarkers. The No Predictable Unpredictable (NPU) threat paradigm is an experimental task designed to distinguish the constructs of fear and anxiety by examining neural/physiological measures in response to threat with predictable or unpredictable timing. Although much of the work on IU and unpredictable threat has focused on self-report data, recent research has found associations between IU and psychophysiological responses to unpredictable threat (i.e., startle) using the NPU-threat task. Despite these findings, research has not examined whether psychophysiological response to unpredictable threat can be mitigated and whether changes in sensitivity to unpredictable threat mediate changes in IU across time. The proposed study will 1) examine sensitivity/responding to unpredictable threat across multiple psychophysiological measures using the NPU-threat task, 2) investigate the ability of each psychophysiological measure to predict individual differences in IU, 3) examine whether an IU-focused intervention alters IU and psychophysiological measures of sensitivity to unpredictable threat, and 4) test the specificity of these relationships in comparison to predictable threat using the NPU-threat task. Responding to unpredictable threat will be assessed using startle and event related potentials (ERPs) to startle probes (i.e., N100 and P300 to startle probes). Seventy participants will undergo a baseline appointment/psychophysiological assessment (High IU N = 50; Low IU N = 20). Following baseline, all individuals will be randomly assigned and undergo a validated1 active or control IU intervention. Participants will also complete a week one (W1) and month one (M1) psychophysiological assessment. Finally, participants will complete self-report measures during their baseline, intervention, W1, and M1 appointments. The most important aspects of this proposal will be in the training that the primary investigator (PI) receives. This training will provide the PI with the necessary skills to integrate psychophysiological research into future work and design and conduct effective clinical trials.